The failure of pancreatic islets of Langerhans to supply insulin in sufficient quantities to maintain blood glucose within physiological limits underlies Type 1 (insulin-dependent) and Type 2 (insulin-independent) diabetes mellitus. Although great strides have been made in the treatment of diabetes since the discoveries of insulin and the insulin receptor, the clinical management of these disorders remains a challenge even under the best of circumstances. As most forms of diabetes are precipitated and/or exacerbated by a reduction in numbers of insulin-secreting beta cells, developing methods that promote beta cell proliferation may lead to the development of new therapies for the estimated 200 million individuals world-wide who live with diabetes. A number of islet growth factors have been reported; many of these are known islet secretagogues as well (e.g., glucose, amino acids), suggesting the possibility that factors released from beta cells act as feedback regulators of islet function. Our preliminary studies suggest that ?-aminobutyric acid (GAGA), long known to be synthesized, stored, and secreted by beta cells, is such a factor. We demonstrate that GABA's effects on islets are mediated through metabotropic GABAB receptors. In contrast to GABA's reputation as a fast inhibitory neurotransmitter, its proliferative action on islets is rather slow (requiring hours); further, GABA appears to work in concert with insulin to stimulate islet proliferation, as its effects are blocked by inhibitors of insulin receptor signaling. Such studies predict that, in the long term, GABA enhances the insulin-releasing capacity of the pancreas. We further demonstrate that, paradoxically, GABA also acts rapidly (seconds to minutes) on islets to inhibit insulin secretion from beta cells. Thus, we suggest the hypothesis that GABA is an endogenous biphasic regulator of islet function. A putative physiological rationale for such dual regulation is that GABA may serve to limit islet proliferation during short exposure to glucose and to encourage it under conditions of frequent or persistent elevations in glucose. Experiments outlined in three Aims will explore this novel hypothesis by defining which GABAB receptor isoforms are expressed in islets and characterizing the signaling pathways underlying their two actions. Understanding the natural biological mechanisms by which islets are regulated is prerequisite to harnessing them for the development of new treatment strategies for diabetes.